C Benini

New strategies for the prevention and treatment of systemic and local bone loss; from pathophysiology to clinical application

Bone loss is the result of a negative unbalance between bone formation ad bone resorption. In the last years, the studies on the Wnt canonical pathway have highlighted its crucial role in bone balance through its influence on the activity and maturation of the osteoblast line and in the Receptor Activator of Nuclear Factor κ B (RANK) - RANK ligand (RANKL)/Osteoprotegerin (OPG) system. These mechanisms are involved not only in the pathological processes inducing not only systemic bone loss (i.e. Postmenopausal osteoporosis, glucocorticoid- induced osteoporosis, etc.), but also at a local level, as happens in Rheumatoid Arthritis (RA). Recently, several new drugs for the treatment of bone loss have been approved, while some others are still under development. The most promising new drugs in the treatment of osteoporosis include the antibody that neutralizes RANKL (denosumab, DMAb), monoclonal antibodies against sclerostin and parathyroid hormone-related protein analogue. Other new strategies for the prevention and treatment of bone loss include calcilytics, cathepsin K inhibitor or the combination or the sequential use of the current drugs. New insights concerning the treatment of the local bone loss in RA and in Complex Regional Pain Syndrome type I are also provided in this review.

In psoriatic arthritis Dkk-1 and PTH are lower than in rheumatoid arthritis and healthy controls

Psoriatic Arthritis (PsA) is characterized by bone erosive damage often associated with exuberant bone formation especially in enthesial sites. Dkk-1 and sclerostin are the main inhibitors of the WNT/β-catenin signaling pathway and play a key role in the regulation of both bone formation and resorption. We performed this study in order to compare the serum levels of the WNT-pathway regulators along with bone turnover markers (BTM) and parathyroid hormone (PTH) between three different groups: one group of female patients affected by PsA, one group of female patients affected by rheumatoid arthritis (RA), and healthy female controls (HC). This is a cross-sectional study including 33 patients with PsA classified with the CASPAR criteria, 35 HC, and 28 patients with RA classified with the ACR/EULAR 2010 criteria. Intact N-propeptide of type I collagen (PINP), C-terminal telopeptide of type I collagen (CTX-I), Dickkopf-related-protein 1 (Dkk-1), sclerostin, PTH, and 25OH-vitamin D serum levels were dosed. The PsA group showed significantly lower Dkk-1 levels when compared to the HC and RA groups. Dkk-1 in the RA group was significantly higher than HC. A similar trend was documented for PTH. In the PsA group, CTX-I was found to be lower than in both the RA and HC groups. This study demonstrated for the first time that Dkk-1 levels in PsA are lower than HC, in contrast with RA, in which they are increased. These results might contribute to explain the different bone involvement of the two different diseases.

Operator-independent quantitative chest computed tomography versus standard assessment of interstitial lung disease related to systemic sclerosis: A multi-centric study

Abstract Purpose. Interstitial lung disease (ILD) related to systemic sclerosis (SSc) is assessed with pulmonary functional tests (PFTs) and semi-quantitative scores based on extent of ILD detectable on chest computed tomography (CT). CT quantitative indexes (QCTIs) are promising tools to assess extent of ILD. This studys aim is to evaluate the validity of QCTI compared with that of chest CT standard evaluation and PFTs. Moreover, QCTI differences between patients’ subgroups according to prognostic stratifications were investigated. Methods. ILD-SSc of patients from six rheumatological clinics was routinely assessed with chest CT and PFTs. Patients were clustered according to prognosis based on functional and/or radiological examinations. Finally, chest CTs were processed with OsiriX in order to obtain QCTI. Results. Two hundred fifty-seven SSc patients were enrolled. QCTI correlation between extent of ILD and PFTs range from − 0.60 to 0.58 and from − 0.54 to 0.52, respectively. The majority of QCTI have a different distribution in patients’ subgroups based on prognosis. Most of QCTI discriminate patients with an ILD severity leading to a poor prognosis. Conclusions. QCTI assessment of ILD-SSc is comparable to the evaluation based on chest CT and/or PFTs. QCTI values corresponding to severe ILD were identified. QCTIs are excellent candidates for a new and more reliable SSc-ILD assessment.

OP0095 Comparison of Interstitial Lung Disease CT Indexes and Pulmonary Function Values in Sistemic Sclerosis Patients: A Multicenter Study

Background Currently, interstitial lung disease (ILD) related to systemic sclerosis (SSc) is assessed with pulmonary function tests (PFTs) and chest Computed Tomography (CT). FVC <70% and DLco <70% were proposed as parameters to define remarkable ILD [1]. Recently, quantitative assessment of ILD extention on chest CT was suggested as reliable parameter for disease assessment [2]. Quantitative score is based on voxel-wise analysis of lung density, summarized in the following quantiatative CT (QCT) parameters: kurtosis (Kurt), skewness (Skew), mean lung attenuation (MLA), standard deviation (Sdev) and fibrosis ratio (FR). Objectives To test the correlation between QCT parameter and PFTs and report the most accurate QCT for ILD assessment. Furthermore, to descibe QCT parameters in patients with FVC and DLco above or below the suggested threshold. Methods 226 SSc patients fullfilling ACR/EULAR diagnosis criteria undewent chest CT and PFTs in six different hospitals. All CTs were processed with an open-source DICOM-viewer (OsiriX) [3] that provided FR and the other QCT parameters (i.e. Kurt, Skew, MLA, Sdev) both related to normal lung parenchyma (nQCT) and to total lung (tQCT). Spearman rank test was used to verify the correlations between QCT parameters and PFTs data. The Mann-Whitney test was used to assess differences between patients with FVC and DLco above or below the suggested threshold. QCT parameters discriminative performances were verified using ROC analysis. A p-value <0.05 was considered significant. Results Among QCT parameters, nKurt showed the best correlation with FVC (r =0,535; p<0,0001) and DLco (r =0,394; p<0,0001). Notably, nKurt was significantly lower in patients with FVC and DLco <70% (p<0.00001). ROC analysis showed that nKurt =1,69 can discriminate very well patients with FVC <70% (sensibility 67,0%, specificity 81,0%). Similarly nKurt =5,25 distiguishes subjects with DLco <70% (sensibility 80,8%, specificity 53,6%). Conclusions QCT parameters correlate with PFTs as reported in literature. In particular, nKurt showed the strongest correlation with FVC and DLco. Furthermore, the proposed thresholds of nKurt could be very useful in clinical practice allowing furhter characterization of ILD associated with SSc. References Khanna D, et al. Arthritis Rheum 2005;52(2):592–600. Ariani A, et al. Rheumatol Int 2013. Rosset A, et al. J Digit Imaging 2004;17(3):205–216. Disclosure of Interest None declared DOI 10.1136/annrheumdis-2014-eular.3048

Quantitative chest computed tomography is associated with two prediction models of mortality in interstitial lung disease related to systemic sclerosis

Objective In this multicentre study, we aimed to evaluate the capacity of a computer-assisted automated QCT method to identify patients with SSc-associated interstitial lung disease (SSc-ILD) with high mortality risk according to validated composite clinical indexes (ILD-Gender, Age, Physiology index and du Bois index). Methods Chest CT, anamnestic data and pulmonary function tests of 146 patients with SSc were retrospectively collected, and the ILD-Gender, Age, Physiology score and DuBois index were calculated. Each chest CT underwent an operator-independent quantitative assessment performed with a free medical image viewer (Horos). The correlation between clinical prediction models and QCT parameters was tested. A value of P < 0.05 was considered statistically significant. Results Most QCT parameters had a statistically different distribution in patients with diverging mortality risk according to both clinical prediction models (P < 0.01). The cut-offs of QCT parameters were calculated by receiver operating characteristic curve analysis, and most of them could discriminate patients with different mortality risk according to clinical prediction models. Conclusion QCT assessment of SSc-ILD can discriminate between well-defined different mortality risk categories, supporting its prognostic value. These findings, together with the operator independence, strengthen the validity and clinical usefulness of QCT for assessment of SSc-ILD.

SAT0445 Short-term effects of secukinumab on bone turnover markers and wnt signaling antagonists in patients with psoriatic arthritis

Background psoriatic arthritis (PsA) is a chronic inflammatory disease characterized also by increased levels of cells producing IL-17 [1], and these levels have been shown to correlate with measures of disease activity and structural damage and bone loss [2]. Secukinumab is a new monoclonal antibody licensed woth the treatment of PsA which selectively binds to and neutralizes interleukin-17 (IL-17). Currently, data about the effects on the activity of either bone-reabsorbing cells and bone-forming cells secondary to the inhibition of the IL-17 pathway are completely absent. Objectives the aim of our study was to explore the short-term effects of secukinumab on bone turnover markers (BTM) and Dkk-1 and sclerostin. Methods we enrolled 28 patients with PsA, classified with the CASPAR criteria and 43 healthy controls (HC). For the PsA group DAS28 was recorded and serum samples were stored at baseline and then at the first, the third and the sixth month of therapy. Intact N-propeptide of type I collagen (PINP) and C-terminal telopeptide of type I collagen (CTX-I). Dickkopf-related-protein 1 (Dkk-1) and sclerostin were dosed too. For the HC group, a single blood sample was taken. Results Neither P1NP nor CTX showed any statistically significant variation. Baseline Dkk-1 for the PsA group was lower than HC. Both Dkk-1 and sclerostin demonstrated a significant increase at the sixth month. When the PsA groups was compared to HC, the difference between the levels of Dkk-1 lost significance at month six.Table 1 Healthy controls (N=43) Dkk-1 pmol/l 25,92±11,26† Sclerostin pmol/l 33,11±16,85 PsA patients (N=28) Baseline values (Mean ± SD) month 1 month 3 month 6 DAS28 3,97±1,30 3,78±1,21 3,57±1,58 3,41±1,55 P1NP ng/ml 43,5±14,5 -0,31±12,91 -0,81±11,97 0,96±14,87 CTX ng/ml 0,25±0,16 0,02±0,14 0,04±0,20 0,08±0,27 Dkk-1 pmol/l 20,0±13,64 -1,45±7,89 -1,38±9,49 2,90±7,45* Sclerostin pmol/l 30,9±12,02 -0,76±8,39 3,09±7,54* 3,03±7,77* *p<0,05 vs baseline, †p<0,05 vs Dkk-1 of the PsA group at baseline, month 1 and month 3. Conclusions our study demonstrated that the treatment with secukinumab has little influence on the levels of BTM within the first six months of treatment but a definite influence on some fine regulators of the bone cells activity such as the WNT inhibitors and it is able, in some way, to normalize the Dkk-1 levels in PsA patients. The clinical implications of this trend are currently unclear thought it might suggest an drug-induced inhibition of the over-proliferation of bone typical of the joint lesions of PsA. Further studies with greater numbers of patients are warranted to determine whether these preliminary results have clinical relevance. References Jandus C, Bioley G, Rivals J-P, et al. Increased numbers of circulating polyfunctional Th17 memory cells in patients with seronegative spondylarthritides. Arthritis Rheum 2008;58:2307–17. doi:10.1002/art.23655. Uluçkan Ö, Jimenez M, Karbach S, et al. Chronic skin inflammation leads to bone loss by IL-17-mediated inhibition of Wnt signaling in osteoblasts. Sci Transl Med 2016;8:330ra37. doi:10.1126/scitranslmed.aad8996. Disclosure of Interest None declared

FRI0485 In peripheral psoriatic arthritis DKK-1 and pth are lower than in rheumatoid arthritis and healthy controls

Background The recent characterization of the canonical WNT pathway in the regulation of bone modeling and remodeling provided important insights for our understanding of the pathophysiology of bone involvement in chronic arthritis [1]. Dkk-1 and sclerostin are the main regulators of WNT/b-catenin signaling, regulating both bone formation and resorption [2]. In a previous our study we showed that in patients with Rheumatoid Arthritis (RA) Dkk-1 is significantly increased and associated with the presence of typical erosions and lower BMD [3]. Objectives we decided to perform this study in order to compare the serum levels of WNT-pathway regulators alongside bone turnover markers (BTM) and Parathyroid Hormone (PTH) between a group of female patients with PsA and healthy controls (HC) or patients with Rheumatoid Arthritis (RA). Methods this is a cross-sectional study including 18 patients with PsA classified with the CASPAR criteria, 35 HC, and 28 patients with RA classified with the ACR/EULAR 2010 criteria. Intact N-propeptide of type I collagen (PINP), C-terminal telopeptide of type I collagen (CTX-I), Dickkopf-related-protein 1 (Dkk-1), sclerostin, PTH and 25OH-Vitamin D serum levels were dosed. All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. Informed consent was obtained from all individual participants included in the study. Results the PsA group showed significantly lower Dkk-1 levels when compared to the HC and RA groups. Dkk-1 in the RA group was also significantly higher than in the HC group. A similar trend was documented also for PTH, however a statistically significant difference was observed only when we comparing the PsA vs RA group (table 1, figure 1). No other statistically significant differences in the other markers were found.Table 1. Values of bone turnover markers (CTX-I, PINP), Dkk-1 and sclerostin of PsA, RA patients and control group (mean ± SD) PsA RA HC P (ANOVA) PINP ng/ml 42,80±16,670 39,19±21,38 42,49±11,52 NS CTX-I ng/ml 0,21±0 ,17 0,32±0,21 0,28±0,10 NS Dkk-1 pmol/l 19,45±11,30 44,51±17,81 27,29±11,48 <0,001 Sclerostin pmol/l 30,82±11,25 30,75±10,25 34,23±17,29 NS PTH pg/ml 21,12±16,63 35,83±13,02 29,69±11,43 <0,005 Conclusions this study demonstrated for the first time that Dkk-1 levels in PsA are lower than HC, in contrast with RA where they are higher. These results might contribute to explain the different bone involvement of the two different diseases. References Xie W, Zhou L, Li S, et al. Wnt/β-catenin signaling plays a key role in the development of spondyloarthritis. Ann N Y Acad Sci 2016;1364:25–31. doi:10.1111/nyas.12968. 2 Spencer GJ, Utting JC, Etheridge SL, et al. Wnt signalling in osteoblasts regulates expression of the receptor activator of NFkappaB ligand and inhibits osteoclastogenesis in vitro. J Cell Sci 2006;119:1283–96. doi:10.1242/jcs.02883. 3 Rossini M, Viapiana O, Adami S, et al. In patients with rheumatoid arthritis, Dickkopf-1 serum levels are correlated with parathyroid hormone, bone erosions and bone mineral density. Clin Exp Rheumatol 2015;33:77–83. Disclosure of Interest None declared

THU0412 Treatment with neridronate in children and adults with osteogenesis imperfecta: data from open-label, not controlled, three-year italian study

Background Osteogenesis Imperfecta (OI) is a rare generalized connective tissue disease. Its main features are skeletal fragility and substantial growth deficiency [1]. Currently, bisphosphonates showed to increase bone mineral density (BMD). A positive effect on prevention of fractures both in adults and in children is reported by some studies, but generally data are still inconsistent [2]. Neridronate is an amino-bisphosphonate licensed in Italy for the treatment of OI. Objectives to assess the long-term efficacy and safety of the treatment in patients with OI. Methods the patients were divided by age into two groups and observed for 3 years: 55 patients younger than 20 years old and 114 patients older than 20 years old. Neridronate was administered by i.v. infusion at the dosage of 2 mg/kg, up to a maximum of 100 mg at three months intervals. DXA of the lumbar spine, hip and ultradistal radius were evaluated every 6 months. Blood calcium, phosphate, bone turnover markers and fasting urinary calcium/creatinine ratio, were obtained at baseline and every 3 months. Results the mean lumbar spine and total hip BMD and BMC significantly increased from baseline up to month 36 in both patients groups. The mean ultradistal radius BMD significantly increased from baseline to any time point in patients younger than 20 years, while, in patients older than 20 years, BMD significantly increased from baseline only at month 18, 30 and 36 respectively. The mean ultradistal radius BMC significantly increased from baseline to any time point in patients younger than 20 years, while there were no substantial or statistically significant changes from baseline to any time point in patients aged older than 20 years. The mean number of fractures observed in the 3 years of treatment was significantly lower than that observed in the 3 years before the start of treatment in both groups (table 1). Most of AEs were symptoms of an acute phase reaction, which was reported in 47.3% of patients younger than 20 years and in 22.8% of those older than 20 years. Serious adverse events (SAEs) were reported in 19 patients (34.5%) younger than 20 years and in 26 patients (22.8%) aged older than 20 years. None of the reported SAEs in both groups was considered as treatment-related.Table 1 , Results of number of fractures per patient during treatment in the two patient populations Number of fractures, mean ± SD (range) Age ≤20 years Age >20 years Before treatment (3 years 2.7±2.37 (0–8) 0.6±1.28 (0–8) During treatment (3 years) 0.9±1.43 (0–7) 0.3±0.56 (0–3) – Wilcoxon signed rank test p-value <0.001 0.003 Conclusions long-term treatment with i.v.neridronate has positive effects on BMD, BMC, bone turnover markers and fracture risk with a good safety profile in both groups. References Hoyer-Kuhn H, Netzer C, Semler O. Osteogenesis imperfecta: pathophysiology and treatment. Wien Med Wochenschr 1946 2015;165:278–84. doi:10.1007/s10354–015–0361-x. Hald JD, Evangelou E, Langdahl BL, et al. Bisphosphonates for the Prevention of Fractures in Osteogenesis Imperfecta: Meta-Analysis of Placebo-Controlled Trials. J Bone Miner Res 2015;30:929–33. doi:10.1002/jbmr.2410. Disclosure of Interest None declared

AB0930 Quantitative Chest Ct in Ild-Ssc Patients with Divergent Risks of Mortality

Background Quantitative analysis of chest CT (QCT) is increasingly applied to characterization of Interstitial Lung Disease (ILD) associated to Systemic Sclerosis (SSc). However, there is no prognostic evidence for QCT in predicting lung detrimental evolution or death. Many Authors proposed composite clinical indexes to predict 1-year mortality. Recently the ILD-GAP index and du Bois index were proven to stratify ILD-SSc patients in outcome-related subgroups. Objectives The main aim of this study was to compare QCT assessment of SSc-ILD and composite clinical indexes in the selection of patients with high risk of mortality. Methods Chest CT, anamnestic data and pulmonary function test of 146 patients with SSc were retrospectively collected and ILD-GAP and DuBois score were calculated. Each chest CT underwent a quantitative assessment. Correlation between clinical prediction models and QCT parameters was tested. p<0,05 was considered statistically significant. Results All QCT parameters had a statistically different distribution in patients with diverging mortality risk according to both clinical prediction models. The cut-off of QCT parameters were calculated by ROC curve analysis, with statistically significant value as compared to clinical prediction models (AUC >0.7, p<0.0001). Conclusions QCT assessment of SSc-ILD can distinguish between different mortality risk categories, therefore it yields prognostic value. These findings, together with the operator-independence, strengthen the accuracy of QCT for assessment of SSc-ILD. Disclosure of Interest None declared

FRI0443 Can Quantitative Chest CT Predict Interstitial Lung Disease Worsening in Systemic Sclerosis? Results from a Multi-Centre Prospective Cohort Study

Background Interstitial Lung Disease (ILD) is the leading cause of morbidity and mortality in Systemic Sclerosis (SSc). Forced Vital Capacity (FVC) and chest Computed Tomography (CT) are the main exams to assess ILD severity. In particular, FVC <70% is associated with a high risk of death. A visual score (VS), based on extension of fibrosis detectable at chest CT>20%, has an unfavourable prognostic value [Goh et al., 2008]. Preliminary evidence supports the usefulness of an automated quantitative CT (QCT) assessment performed with a medical software, OsiriX, in identifying patients with more severe SSc-ILD [Ariani et al. 2014] Objectives The aim of this work is to investigate whether QCT can predict ILD-SSc radiological and functional worsening over time. Methods One hundred forty-nine patients with SSc according to EULAR/ACR criteria underwent chest CTs and pulmonary functional tests at baseline (t0) and after 1 year (t1). A VS was evaluated for each chest CT; the quantitative assessment, in order to obtain QCT indexes (QCTI), was performed only in chest CT done in t0. Patients were clustered in 3 groups: 1) VS <20% both at t0 and t1; 2) radiological worsening (defined as the increase of the visual score, between t0 and t1, from <20% to >20% values); 3)VS>20% both at t0 and t1. A similar subdivision in other three groups was performed on the basis of FVC values (with 70% as cutoff).The Kolmogorov-Smirnov test was used to investigate QCTI distribution in the above mentioned groups. A p-value <0.05 was considered significant. Results In group 1 (clustered according to VS variation) QCTI were different from the ones of the other two groups (p<0.001). Group 2 and 3 QCTI were not statistically different. Similar results were observed when patients were clustered according to FVC values: group1 was different from group 2 and 3 (p<0.05) but the last ones were not statistically different. Figure A shows kurtosis (one of the QCTI) distribution in the groups. Conclusions In spite of the limitations of this study (short follow up compared with the slow ILD-SSc progression) our results support the predictivity of a QCTI in terms of future radiological and functional ILD worsening. Given its reliability and easy access, quantitative CT assessment of ILD is a promising candidate in the assessment and prognostic stratification of SSc-ILD, even in clinical practice. Disclosure of Interest None declared